Streptococcus pneumoniae is the most common cause of community-acquired pneumonia accounting for 40,000 deaths/year in the US. Individuals who are most susceptible to pneumococcal pneumonia include those who are energy malnourished as a secondary consequence of chronic diseases such as cancer, emphysema, and AIDS. The mechanisms responsible for impaired innate immunity against bacterial infections arising from energy malnutrition are poorly understood. Leptin is a hormone produced by adipose tissue that is reduced in the energy malnourished and is known to regulate innate immune responses. We have observed that mice rendered leptin-deficient by genetic means or by fasting are more susceptible to bacterial pneumonia and alveolar macrophages (AMs) and neutrophils (PMNs) obtained from these animals exhibit defects in phagocytosis and killing of bacteria in vitro. The exogenous administration of leptin in vivo to leptin-deficient and fasted mice reconstitutes antibacterial host defense endpoints in vivo and in vitro. Our global hypothesis is that leptin regulates AM and PMN effector functions, PMN recruitment, and cytokine and leukotriene synthesis in the innate immune response against S. pneumoniae in vivo and in vitro. To test this hypothesis we will explore the following aims: 1) Assess the role of endogenous leptin in pulmonary host defense against S. pneumoniae by blocking leptin receptor signaling in vivo using a pharmacologic agent and leptin receptor transgenic mice; 2) Determine the kinetics and cellular sources of leptin produced during the course of pneumococcal pneumonia and the target cells in the lung for leptin activity; 3) Examine the effect of distinct leptin receptor signaling pathways in AM and PMN effector functions against S. pneumoniae in vitro using cells from leptin receptor transgenic mice; and 4) Determine the effects of leptin administered at different time points following S. pneumoniae administration on bacterial clearance, survival, and mechanisms of AM and PMN effector functions in WT mice. These studies will provide novel insights into the mechanisms by which leptin regulates innate immune responses against bacterial pathogens and will test the use of exogenous leptin as an adjunctive therapeutic agent in the treatment of pneumococcal pneumonia.